Accepted Article
Article Type: Invited Review
Pathogenesis of atopic dermatitis
Wenming Peng, Natalija Novak* Department of Dermatology and Allergy, University of Bonn, Bonn, Germany.
*Correspondence to: Natalija Novak, Department of Dermatology and Allergy, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Tel.: +49 228 287 15370, Fax.: +49 228 287 14333, E-mail: [email protected]
ABBREVIATIONS Antigen presenting cells, APCs; Atopic dermatitis, AD; Dendritic cells, DCs; Free fatty acid, FFA; Filaggrin, FLG; Inflammatory epidermal dendritic cells, IDECs; Innate lymphoid cells, ILCs; Group 2 innate lymphoid cells, ILC2s; Langerhans cells, LCs; Lymph nodes, LN; Mast cells, MCs; Macrophages, Mɸs; Single nucleotide polymorphism, SNP; Tight junction, TJ; Thymic stromal lymphopoietin, TSLP; TNFlike weak inducer of apoptosis, TWEAK
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SUMMARY
Atopic dermatitis (AD) is the most common allergic inflammatory skin disease. Interactions of genetic, environmental and immunological factors result in the initiation and progress of AD. Although the clinical picture, characterized by acute flare ups of eczematous, pruritic lesions on dry skin at typical predilection such as the flexural folds, is quite homogenous, the trigger factors of the disease are diverse and the pathophysiologic network involved is complex. Therefore, first attempts have been made to classify subtypes of AD based on the most relevant causal factors in the individual patient. To optimize such a stratification of patients, detailed knowledge about cofactors impacting on both, manifestation of AD as well as impairment of the course of the disease is indispensable. AD shares general features of barrier dysfunction and skin inflammation with other inflammatory diseases of the skin such as psoriasis or allergic contact dermatitis, but a plethora of disease specific genetic, immunologic and environmental factors have been identified in AD as well. It is the purpose of this review to illustrate key concepts of the pathogenesis of AD. Important findings of recent years will be summarized and co-factors of the pathogenesis will be controversially discussed. We will summarize knowledge on pathogenetic factors on the immunologic level contributing to skin barrier dysfunction in AD and the role of the microbiome as first line of defense. Furthermore, we will elucidate the role of innate lymphoid cells in AD and outline the pattern of T helper cell subtypes present in the skin during different stages of AD.
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Introduction Atopic dermatitis (AD) is a chronic disease of the skin based on skin barrier dysfunction, which leads together with environmental factors and multiple changes of the immune system to eczematous and itchy lesions at the flexural folds and other typical distributions [1]. Acute flare-ups and exacerbations as well as chronic eczematous skin lesions on dry skin accompanied by intensive pruritus characterize the course. AD might vary from mild forms to moderate and severe forms and diagnosis as well as severity can be defined with the help of standardized criteria and scoring systems. AD occurs in childhood only, lasts until adulthood or manifests even for the first time during adulthood. Different course types have been identified so far [1]. Although the clinical picture, characterized by acute flare ups of eczematous, pruritic lesions on dry skin at typical predilection such as the flexural folds, is quite homogenous, the trigger factors of the disease are diverse and the pathophysiologic network involved is quite complex. Therefore, first attempts have been made to classify subtypes of AD based on the most relevant causal factors in the individual patient. To optimize such a stratification of patients, detailed knowledge about cofactors impacting on both, manifestation of AD as well as impairment of the course of the disease is indispensable. A plethora of epidemiologic factors such as nutritional factors [2], number of siblings, social status, urban settings or climatic aspects have been described to impact on the risk for AD [3]. Most knowledge has been gained in recent times concerning immunologic mechanisms involved in the pathophysiology of AD. Increased infiltration of T cells, DC subtypes, macrophages (Mɸs), mast cells (MCs) and eosinophils can be observed in AD lesions as well as increased amount of different cytokines and chemokines [5]. Cytokine interaction and cellular crosstalk have been shown in recent studies. In this article, we will discuss new findings and controversial issues concerning the pathogenesis of AD. This article is protected by copyright. All rights reserved.
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polymorphisms (SNPs) in the IFNG and IFNGR1 were significantly associated with eczema herpeticum [32], which is based on a higher susceptibility to HSV skin infection of a subgroup of AD patients. Keratinocytes of patients with AD exhibit increased IFN-γ–induced apoptosis compared with keratinocytes from healthy subjects. Three apoptosis-related genes (NOD2, DUSP1, and ADM) and 8 genes overexpressed in AD skin lesions (CCDC109B, CCL5, CCL8, IFI35, LYN, RAB31, IFITM1, and IFITM2) were induced by IFN-γ in primary keratinocytes [33]. Modified gene expression of filaggrin, loricin, involucrin, corneodesmosin or late cornified envelope protein mirror disturbed keratinocyte differentiation in AD [34].
Not only the skin itself, but already microbes colonizing the skin represent the first line of the skin barrier. Interaction of microbes with the skin immune system is important for the pathogenesis of AD. Due to different factors, such as higher pH and a Th2 dominated micromilieu elevated amounts of Staphylococcus aureus (S. aureus) are detectable on AD skin [35, 36]. Furthermore, S. aureus dampens skin barrier function by releasing virulence factors such as α-toxin to induce cell death of keratinocytes [37] and to promote Th2-type inflammation [3825]. After treatment and improvement of skin lesions, Propionbacteriae, Corynebacteriae and Streptococci are detectable in increased amounts on AD skin [39-41]. Birth mode, birth order, number of siblings and breast feeding were identified as potential co-factors impacting on the gut microbiome. While colonization with Lactobacilli and Bacteroides increased with the number of siblings, colonization with Clostridia decreased [42].
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47. Niebuhr M, Langnickel J, Draing C et al. Dysregulation of toll-like receptor-2 (TLR-2)-induced effects in monocytes from patients with atopic dermatitis: impact of the TLR-2 R753Q polymorphism. Allergy. 2008; 63:728-734. 48. Kaesler S, Volz T, Skabytska Y et al. Toll-like receptor 2 ligands promote chronic atopic dermatitis through IL-4-mediated suppression of IL-10. J Allergy Clin Immunol. 2014; 134:92-99. 49. Brandt EB, Gibson AM, Bass S et al. Exacerbation of allergen-induced eczema in TLR4- and TRIF-deficient mice. J Immunol. 2013; 191: 3519-3525. 50. Dai X, Sayama K, Tohyama M et al. Mite allergen is a danger signal for the skin via activation of inflammasome in keratinocytes. J Allergy Clin Immunol. 2011; 127: 806-814. 51. Roth SA, Simanski M, Rademacher F et al. The pattern recognition receptor NOD2 mediates Staphylococcus aureus-induced IL-17C expression in keratinocytes. J Invest Dermatol. 2014; 134: 374-380. 52. Varga A, Budai MM, Milesz S et al. Ragweed pollen extract intensifies lipopolysaccharide-induced
priming
of
NLRP3
inflammasome
in
human
macrophages. Immunology. 2013; 138: 392-401. 53. Niebuhr M, Baumert K, Heratizadeh A et al. Impaired NLRP3 inflammasome expression and function in atopic dermatitis due to Th2 milieu. Allergy. 2014; 69: 1058-1067. 54. Berroth A, Kühnl J, Kurschat N et al. Role of fibroblasts in the pathogenesis of atopic dermatitis. J Allergy Clin Immunol. 2013; 131: 1547-1554.
This article is protected by copyright. All rights reserved.
Accepted Article This article is protected by copyright. All rights reserved.
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polymorphisms (SNPs) in the IFNG and IFNGR1 were significantly associated with eczema herpeticum [32], which is based on a higher susceptibility to HSV skin infection of a subgroup of AD patients. Keratinocytes of patients with AD exhibit increased IFN-γ–induced apoptosis compared with keratinocytes from healthy subjects. Three apoptosis-related genes (NOD2, DUSP1, and ADM) and 8 genes overexpressed in AD skin lesions (CCDC109B, CCL5, CCL8, IFI35, LYN, RAB31, IFITM1, and IFITM2) were induced by IFN-γ in primary keratinocytes [33]. Modified gene expression of filaggrin, loricin, involucrin, corneodesmosin or late cornified envelope protein mirror disturbed keratinocyte differentiation in AD [34].
Not only the skin itself, but already microbes colonizing the skin represent the first line of the skin barrier. Interaction of microbes with the skin immune system is important for the pathogenesis of AD. Due to different factors, such as higher pH and a Th2 dominated micromilieu elevated amounts of Staphylococcus aureus (S. aureus) are detectable on AD skin [35, 36]. Furthermore, S. aureus dampens skin barrier function by releasing virulence factors such as α-toxin to induce cell death of keratinocytes [37] and to promote Th2-type inflammation [3825]. After treatment and improvement of skin lesions, Propionbacteriae, Corynebacteriae and Streptococci are detectable in increased amounts on AD skin [39-41]. Birth mode, birth order, number of siblings and breast feeding were identified as potential co-factors impacting on the gut microbiome. While colonization with Lactobacilli and Bacteroides increased with the number of siblings, colonization with Clostridia decreased [42].
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At present, data about the skin microbiome are premature and there is not much detailed knowledge about differences of the skin microbiome during different stages of AD and which components besides S. aureus might promote the disease.
Immune reactivity Innate immunity in the pathogenesis of AD Expression and function of pattern recognition receptors on skin cells in AD is altered due to genetic modification [43] but also due to secondary factors such as cytokines and chemokines in the micromilieu [44, 45]. TLR signalling is not only important for host defence mechanisms of the innate immune system but also for the epidermal barrier function [40]. Moreover, activation of TLR2 on monocytes and Mɸs of patients with AD leads to different cytokine and chemokine responses as compared to healthy individuals [45, 47]. So far, it is not completely clear, which mechanisms control the development of acute AD to chronic AD. A recent study demonstrates that activation of TLR2 on DCs converts Th2 type dermatitis to chronic cutaneous inflammation in a mouse model [48]. Concerning TLR4, in an allergen-induced mouse model, mice deficient of TLR4 display more severe AD-like symptoms and skin inflammation [49]. Accumulating evidence indicates that inflammasomes are involved in the pathogenesis of AD. Activation of the inflammasome in keratinocytes by allergens [50] and S. aureus [51], as well as in Mɸs after exposure to ragweed pollen allergen has been shown [52]. Current knowledge suggests inflammasomes promote Th1- or Th17-mediated inflammation that may be important for acute AD [51, 53]. Moreover, expression of human β-defensins and cathelicidins is lower in AD skin as in other chronic inflammatory skin diseases [1]. The reduced expression has been
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linked to a higher risk of AD patients to develop bacterial or viral skin infections and results in part from the Th2 dominated micromilieu in AD skin.
Functions of skin immune cells in the pathogenesis of AD Inflammatory AD skin contains vast numbers of resident and infiltrated immune cells, such as LCs, inflammatory epidermal dendritic cells (IDECs), Mɸs, MCs, neutrophils, basophils, eosinophils, Innate lymphoid cells (ILCs), natural killer cells, fibroblast [54] and various T cell subsets. Functional interactions of skin immune cells are essential for the pathogenesis of AD. The role of IgE in AD is still a matter of debate, since it is not clear if it plays a central role in the pathogenesis of AD or just a bystander phenomenon. In fact, allergen specific IgE to food or aeroallergens is detectable in a subgroup of patients with AD and allergen challenge in form of oral provocation or epicutaneous exposure leads to development or impairment of skin lesions. Among skin immune cells, DCs are the most important cell type to initiate Th2 immune responses [5, 55-56]. A hallmark of epidermal and dermal DCs in AD is the expression of the high affinity receptor for IgE (FcεRI) on the cell surface. Receptor expression increases with severity of the skin lesions and enable the cells to take up IgE and via IgE allergens [5]. After allergen challenge or onset of inflammation due to other trigger factors, the number of Langerin- DCs, FcεRI+ DC increases in the epidermis and dermis. Inflammatory DCs are regarded as main amplifier of allergic inflammation on the level of DCs. In vitro studies demonstrated that allergen challenge of inflammatory DCs subtypes increases the release of pro-inflammatory cytokines and chemokines [5]. As a result, allergen specific T cells expressing skin
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homing factor CLA are detectable in skin lesions of AD patients with clinically relevant sensitizations after allergen challenge [57, 58]. Structural similarities between exogenous proteins, of which several have been identified, and endogenous proteins have introduced the concept of IgE autoreactivity in a subgroup of atopic dermatitis patients. In a recent systematic review of 8 studies involving 634 atopic dermatitis patients and 173 control subjects, auto-IgE to keratinocyte-derived self-antigens were observed in 38.2% of the patients, most of whom were adults with persistent moderate to severe disease [59]. Thus, the time point of development of IgE autoreactivity and its contribution to the chronicity of atopic dermatitis needs to be investigated in further studies.
A recent 3D skin structure study demonstrates that in AD skin, LCs are present in the higher layers of the epidermis and penetrate skin TJ to sense outside antigen with their dendrites, while inflammatory DC subtypes are located at lower parts, suggesting different pathophysiological functions of LCs and inflammatory DCs [60, 61]. Together, current results support a model in which LCs provide important regulatory functions in a steady state, while they are also capable to contribute to T cell responses upon activation. Human monocytes are regarded as precursors of Mɸs and DCs for a long time because monocytes differentiate into Mɸs and DCs under an inflammatory milieu. Recent studies add new information by showing that in (1) normal tissue resident LCs and Mɸs are derived embryonically and renew themselves via proliferation [62, 63] and (2) in steady-state, monocytes migrated from blood to tissue keep their monocytic character, and present tissue antigen to draining lymph nodes (LNs) [64]. Therefore, attenuated IFN-γ [65] and TGF-β [66] signaling and responsiveness of human monocytes from AD patients might promote Th2 immune responses due to This article is protected by copyright. All rights reserved.
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decreased TGF-β signalling on one hand and impaired Th1 cytokine IFN-γ stimulation on the other hand. MCs are the key cells to mediate type I hypersensitivity reactions. Results from animal models demonstrate MCs are required for the development of AD-like skin lesion [67]. Number of MCs in lesional AD skin is increased, in particular of mast cells releasing IL-31, which supports the hypothesis that MCs promote skin inflammation in AD [68]. In AD skin, δ-toxin released by S. aures stimulates MC degranulation, which promotes local inflammation by release of proinflammatory mediators [69]. The role of basophils in AD is still unclear [68]. Recently, ILCs have been observed to infiltrate AD skin and to release Th2 type cytokines IL-5, IL-9 and IL-13 to promote local inflammation after stimulation with allergen, TSLP or IL-33 [70, 71]. IL-4 and IL-13 are the main mediators of Th2 driven immune response and signalling of both cytokines take part via the common IL-4 receptor α (IL-4Rα). IL4Rα mediates among several other mechanisms IgE production by B cells, dendritic cells differentiation, activation of T cells as well as recruitment of eosinophils. Consequently, inhibition of IL-4Rα mediated mechanisms would represent an plausible therapeutic target, which is currently under investigation in ongoing clinical studies [72, 73].
Interplay of immune responses in the pathogenesis of AD skin Upon stimulation with allergens, skin barrier derived-TSLP stimulates DCs to derive Th2 responses [27, 74]. Dramatic infiltration of Th2 T cells into acute AD skin, together with moderate infiltration with Th22 cells and few Th17 cells was observed. Data from atopy patch testing and other studies have proven that chronic AD is
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associated with a mixed immune response consisting of Th2/Th1/Th22 cells infiltrating the skin [34, 75] (Figure 2). Relatively small numbers of Th17 cells are present in AD skin, but the function of IL17 in the pathogenesis of AD is unclear. The observation that IL-17A suppresses expression of TSLP and Th2 cytokines, and Th2 cytokine IL-4 suppresses IL-17A function in a human skin model [76] suggests that the Th17 and Th2 pathways might coregulate each other. However, IL-17A deficient mice display attenuated Th2 responses in the acute phase of skin inflammation [77]. More results from other animal models and human systems are necessary to unravel the role of Th17 cells in AD. Interestingly, IL25 (IL-17E), an important and distinct member of the IL17 family, promotes Th2 cell-mediated inflammation by activating Th2 memory cells together with TSLP-activated DCs [78]. Furthermore, IL-25 decreases filaggrin synthesis in keratinocytes [79]. IL-33 and TSLP are tissue derived cytokines which are essential for the pathogenesis of AD by promoting local Th2 cell derived inflammation [80].
Moreover, histamine, which is released by MCs upon allergen challenge but also by other skin cells might activate macrophage like cells and promote the release of inflammatory cytokines via histamine receptor expression on the surface of those cells [81]. The chemokine pattern of DCs subsets differs profoundly between acute and chronic AD and non-lesional AD skin. Chemokines such as CCL17, CCL22 increase in the skin during inflammation and drive the recruitment of inflammatory DCs subtypes as well as T cell infiltration [82]. Data from in vitro studies with skin DCs indicate that unstimulated DCs of AD patients are capable to drive either Th1,
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Th2 or Th17 immune responses, while the local micromilieu impacts on their T cell polarization in vivo [83].
Microbiology Risk factors for complications A subgroup of patients with AD is at risk for the development of severe disseminated virus infections of the skin induced by herpes simplex virus, called eczema herpeticum (EH). From the clinical features, these patients display higher specific and total IgE serum levels. Furthermore, SNPs in IFNG and IFNGR1 as well as interferon regulatory factor (IRF)2 were associated with EH [32, 84]. Attenuated responsiveness of DCs isolated from lesional AD skin mirrored by lower STAT1 phosphorylation and induction of IFN-γ regulated genes has been demonstrated and might result from the Th2 dominance as well as support the Th2 dominance in AD skin [65]. In addition, higher IL-25 expression in the skin of patients with AD who underwent one or more episodes of EH has been identified as another risk factor. In vitro, IL-25 in combination with IL-4 or IL-13 enhances HSV replication and reduces filaggrin break down products, which have been demonstrated to counteract HSV and vaccinia replication [85]. Elevated number of functional Tregs as well as CD14dimCD16+ monocytes with attenuated capacity to produce proinflammatory cytokines has been demonstrated in acute EH [86].
Conclusion Pathogenesis of AD results from genetic, environmental as well as immunological factors. Vast immune cell types spatially and temporally coordinate each other in
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inflammatory AD skin. Further identification of this interplay on the organic, cellular and molecular level will help to develop new therapeutic approaches.
Figures Figure 1. Graphic summary of effects of skin barrier on the pathogenesis of AD. Genetic and immunologic as well as mechanical factors such as scratching induce skin barrier damage, allowing contact of skin resident antigen presenting cells to allergens, bacterial and viral antigens as well as other environmental factors. Activated antigen presenting cells migrate to lymph nodes and prime naive T cells into Th2 cells. Elevated Th2 cytokines together with TNF-α and IFN-γ further damage skin barrier functions by inducing apoptosis of keratinocytes as well as impair the function of tight junctions, and promote Th2 responses by enhancing TSLP expression of epithelial cells. Moreover, colonizing pathogens such as S. aureus impair barrier function through the release of virulence factors to induce keratinocyte death and to boost Th2-type inflammation. Together, genetic and immunological factors contribute to the skin barrier dysfunction and play a major role in the pathogenesis of AD.
Figure 2. Summary of pathogenetic mechanisms in acute and chronic AD. (a). In the acute phase of AD, high amount of invading allergens through damaged skin barrier stimulates mast cells to degranulate and to release inflammatory mediators such as histamine, PGD2, IL-6, IL-8 and TNF-α as well as IL-31. Damaged skin epithelial cells release TSLP which further enhances Th2 type skin inflammation. In response to invading allergens, skin resident LCs and keratinocytes release inflammatory cytokines including IL-12 and IL-18 as well as chemokines to attract other types of immune cells, such as Mɸs, basophils, eosinophils and neutrophils as This article is protected by copyright. All rights reserved.
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well as T cells. Although Th1, Th2, Th17 and Th22 responses co-exist in acute AD skin, Th2 type responses contribute mainly to the pathogenesis of acute AD by mediating type 2 skin inflammation. (b). Th1, Th2, Th17 and Th22 responses are involved in the pathogenesis of chronic AD. Proinflammatory cytokines such as IL-12 and IL-18 secreted by skin DCs support Th1 activation. IFN-γ secreted by Th1 cells induces keratinocyte apoptosis, while activation of Th22 cells induces skin remodeling and thickness of chronic AD skin.
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47. Niebuhr M, Langnickel J, Draing C et al. Dysregulation of toll-like receptor-2 (TLR-2)-induced effects in monocytes from patients with atopic dermatitis: impact of the TLR-2 R753Q polymorphism. Allergy. 2008; 63:728-734. 48. Kaesler S, Volz T, Skabytska Y et al. Toll-like receptor 2 ligands promote chronic atopic dermatitis through IL-4-mediated suppression of IL-10. J Allergy Clin Immunol. 2014; 134:92-99. 49. Brandt EB, Gibson AM, Bass S et al. Exacerbation of allergen-induced eczema in TLR4- and TRIF-deficient mice. J Immunol. 2013; 191: 3519-3525. 50. Dai X, Sayama K, Tohyama M et al. Mite allergen is a danger signal for the skin via activation of inflammasome in keratinocytes. J Allergy Clin Immunol. 2011; 127: 806-814. 51. Roth SA, Simanski M, Rademacher F et al. The pattern recognition receptor NOD2 mediates Staphylococcus aureus-induced IL-17C expression in keratinocytes. J Invest Dermatol. 2014; 134: 374-380. 52. Varga A, Budai MM, Milesz S et al. Ragweed pollen extract intensifies lipopolysaccharide-induced
priming
of
NLRP3
inflammasome
in
human
macrophages. Immunology. 2013; 138: 392-401. 53. Niebuhr M, Baumert K, Heratizadeh A et al. Impaired NLRP3 inflammasome expression and function in atopic dermatitis due to Th2 milieu. Allergy. 2014; 69: 1058-1067. 54. Berroth A, Kühnl J, Kurschat N et al. Role of fibroblasts in the pathogenesis of atopic dermatitis. J Allergy Clin Immunol. 2013; 131: 1547-1554.
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55. Phythian-Adams AT, Cook PC, Lundie RJ et al. CD11c depletion severely disrupts Th2 induction and development in vivo. J Exp Med. 2010; 207: 2089-2096. 56. Hammad H, Plantinga M, Deswarte K et al. Inflammatory dendritic cells--not basophils--are necessary and sufficient for induction of Th2 immunity to inhaled house dust mite allergen. J Exp Med. 2010; 207: 2097-2111. 57. Reekers R, Busche M, Wittmann M et al. Birch pollen-related foods trigger atopic dermatitis in patients with specific cutaneous T-cell responses to birch pollen antigens. J Allergy Clin Immunol. 1999; 104: 466-472. 58. Werfel T, Ahlers G, Schmidt P et al. Milk-responsive atopic dermatitis is associated with a casein-specific lymphocyte response in adolescent and adult patients. J Allergy Clin Immunol. 1997; 99: 124-133. 59. Tang TS, Bieber T, Williams HC. Are the concepts of induction of remission and treatment of subclinical inflammation in atopic dermatitis clinically useful? J Allergy Clin Immunol. 2014; 133: 1615-1625. 60. Kubo A, Nagao K, Yokouchi M et al. External antigen uptake by Langerhans cells with reorganization of epidermal tight junction barriers. J Exp Med. 2009; 206:2937246. 61. Yoshida K, Kubo A, Fujita H et al. Distinct behavior of human Langerhans cells and inflammatory dendritic epidermal cells at tight junctions in patients with atopic dermatitis. J Allergy Clin Immunol. 2014; 134: 856-864. 62. Chorro L, Sarde A, Li M et al. Langerhans cell (LC) proliferation mediates neonatal development, homeostasis, and inflammation-associated expansion of the epidermal LC network. J Exp Med. 2009; 206: 3089-3100.
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63. Hashimoto D, Chow A, Noizat C et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity. 2013; 38: 792-804. 64. Jakubzick C, Gautier EL, Gibbings SL et al. Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes. Immunity. 2013; 39:599-610. 65. Gros E, Petzold S, Maintz L et al . Reduced IFN-γ receptor expression and attenuated IFN-γ response by dendritic cells in patients with atopic dermatitis. J Allergy Clin Immunol. 2011; 128: 1015-1021. 6655. Peng WM, Maintz L, Allam JP et al. Attenuated TGF-β1 responsiveness of dendritic cells and their precursors in atopic dermatitis. Eur J Immunol. 2013; 43:1374-1382. 67. Ando T, Matsumoto K, Namiranian S et al. Mast cells are required for full expression of allergen/SEB-induced skin inflammation. J Invest Dermatol. 2013; 133: 2695-2705. 68. Otsuka A, Kabashima K. Mast cells and basophils in cutaneous immune responses. Allergy. 2014. doi: 10.1111/all.12526. 69. Nakamura Y, Oscherwitz J, Cease KB et al. Staphylococcus δ-toxin induces 70. Imai Y, Yasuda K, Sakaguchi Y et al. Skin-specific expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice. Proc Natl Acad Sci U S A. 2013;110:13921-13926. 71. Salimi M, Barlow JL, Saunders SP et al. A role for IL-25 and IL-33-driven type-2 innate lymphoid cells in atopic dermatitis. J Exp Med. 2013;210:2939-2950. This article is protected by copyright. All rights reserved.
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72. Beck LA, Thaçi D, Hamilton JD et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med. 2014; 371: 130-139. 73. Hamilton JD, Suárez-Fariñas M, Dhingra N et al. Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis. J Allergy Clin Immunol. 2014; 134: 1293-1300. 74. Oyoshi MK, Larson RP, Ziegler SF et al. Mechanical injury polarizes skindendritic cells to elicit a T(H)2 response by inducing cutaneous thymic stromal lymphopoietin expression. J Allergy Clin Immunol. 2010; 126: 976-984. 75. Gittler JK, Shemer A, Suárez-Fariñas M et al. Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis. J Allergy Clin Immunol. 2012; 130: 1344-1354. 76. Eyerich K, Pennino D, Scarponi C et al. IL-17 in atopic eczema: linking allergenspecific adaptive and microbial-triggered innate immune response. J Allergy Clin Immunol. 2009; 123: 59-66. 77. Nakajima S, Kitoh A, Egawa G et al. IL-17A as an inducer for Th2 immune responses in murine atopic dermatitis models. J Invest Dermatol. 2014; 134: 21222130. 78. Wang YH, Angkasekwinai P, Lu N et al. IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells. J Exp Med. 2007; 204: 1837-1847. 79. Hvid M, Vestergaard C, Kemp K et al. IL-25 in atopic dermatitis: a possible link between inflammation and skin barrier dysfunction? J Invest Dermatol. 2011; 131:150-157.
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80. Kinoshita H, Takai T, Le TA et al. Cytokine milieu modulates release of thymic stromal lymphopoietin from human keratinocytes stimulated with double-stranded RNA. J Allergy Clin Immunol. 2009; 123:179. 81. Novak N, Peng WM, Bieber T et al. FcεRI stimulation promotes the differentiation of histamine receptor 1-expressing inflammatory macrophages. Allergy. 2013; 68:454-461. 82. Gros E, Bussmann C, Bieber T et al. Expression of chemokines and chemokine receptors in lesional and nonlesional upper skin of patients with atopic dermatitis. J Allergy Clin Immunol. 2009; 124: 753-760. 83. Fujita H, Shemer A, Suárez-Fariñas M et al. Lesional dendritic cells in patients with chronic atopic dermatitis and psoriasis exhibit parallel ability to activate T-cell subsets. J Allergy Clin Immunol. 2011;128:574-582. 84. Gao PS, Leung DY, Rafaels NM et al. Genetic variants in interferon regulatory factor 2 (IRF2) are associated with atopic dermatitis and eczema herpeticum. J Invest Dermatol. 2012; 132:650-657. 85. Kim BE, Bin L, Ye YM et al. IL-25 enhances HSV-1 replication by inhibiting filaggrin expression, and acts synergistically with Th2 cytokines to enhance HSV-1 replication. J Invest Dermatol. 2013; 133: 2678-2685. 86. Takahashi R, Sato Y, Kurata M et al. Pathological role of regulatory T cells in the initiation and maintenance of eczema herpeticum lesions. J Immunol. 2014; 192: 969-978.
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Article Type: Invited Review
Pathogenesis of atopic dermatitis
Wenming Peng, Natalija Novak* Department of Dermatology and Allergy, University of Bonn, Bonn, Germany.
*Correspondence to: Natalija Novak, Department of Dermatology and Allergy, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Tel.: +49 228 287 15370, Fax.: +49 228 287 14333, E-mail: [email protected]
ABBREVIATIONS Antigen presenting cells, APCs; Atopic dermatitis, AD; Dendritic cells, DCs; Free fatty acid, FFA; Filaggrin, FLG; Inflammatory epidermal dendritic cells, IDECs; Innate lymphoid cells, ILCs; Group 2 innate lymphoid cells, ILC2s; Langerhans cells, LCs; Lymph nodes, LN; Mast cells, MCs; Macrophages, Mɸs; Single nucleotide polymorphism, SNP; Tight junction, TJ; Thymic stromal lymphopoietin, TSLP; TNFlike weak inducer of apoptosis, TWEAK
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SUMMARY
Atopic dermatitis (AD) is the most common allergic inflammatory skin disease. Interactions of genetic, environmental and immunological factors result in the initiation and progress of AD. Although the clinical picture, characterized by acute flare ups of eczematous, pruritic lesions on dry skin at typical predilection such as the flexural folds, is quite homogenous, the trigger factors of the disease are diverse and the pathophysiologic network involved is complex. Therefore, first attempts have been made to classify subtypes of AD based on the most relevant causal factors in the individual patient. To optimize such a stratification of patients, detailed knowledge about cofactors impacting on both, manifestation of AD as well as impairment of the course of the disease is indispensable. AD shares general features of barrier dysfunction and skin inflammation with other inflammatory diseases of the skin such as psoriasis or allergic contact dermatitis, but a plethora of disease specific genetic, immunologic and environmental factors have been identified in AD as well. It is the purpose of this review to illustrate key concepts of the pathogenesis of AD. Important findings of recent years will be summarized and co-factors of the pathogenesis will be controversially discussed. We will summarize knowledge on pathogenetic factors on the immunologic level contributing to skin barrier dysfunction in AD and the role of the microbiome as first line of defense. Furthermore, we will elucidate the role of innate lymphoid cells in AD and outline the pattern of T helper cell subtypes present in the skin during different stages of AD.
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Introduction Atopic dermatitis (AD) is a chronic disease of the skin based on skin barrier dysfunction, which leads together with environmental factors and multiple changes of the immune system to eczematous and itchy lesions at the flexural folds and other typical distributions [1]. Acute flare-ups and exacerbations as well as chronic eczematous skin lesions on dry skin accompanied by intensive pruritus characterize the course. AD might vary from mild forms to moderate and severe forms and diagnosis as well as severity can be defined with the help of standardized criteria and scoring systems. AD occurs in childhood only, lasts until adulthood or manifests even for the first time during adulthood. Different course types have been identified so far [1]. Although the clinical picture, characterized by acute flare ups of eczematous, pruritic lesions on dry skin at typical predilection such as the flexural folds, is quite homogenous, the trigger factors of the disease are diverse and the pathophysiologic network involved is quite complex. Therefore, first attempts have been made to classify subtypes of AD based on the most relevant causal factors in the individual patient. To optimize such a stratification of patients, detailed knowledge about cofactors impacting on both, manifestation of AD as well as impairment of the course of the disease is indispensable. A plethora of epidemiologic factors such as nutritional factors [2], number of siblings, social status, urban settings or climatic aspects have been described to impact on the risk for AD [3]. Most knowledge has been gained in recent times concerning immunologic mechanisms involved in the pathophysiology of AD. Increased infiltration of T cells, DC subtypes, macrophages (Mɸs), mast cells (MCs) and eosinophils can be observed in AD lesions as well as increased amount of different cytokines and chemokines [5]. Cytokine interaction and cellular crosstalk have been shown in recent studies. In this article, we will discuss new findings and controversial issues concerning the pathogenesis of AD. This article is protected by copyright. All rights reserved.
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polymorphisms (SNPs) in the IFNG and IFNGR1 were significantly associated with eczema herpeticum [32], which is based on a higher susceptibility to HSV skin infection of a subgroup of AD patients. Keratinocytes of patients with AD exhibit increased IFN-γ–induced apoptosis compared with keratinocytes from healthy subjects. Three apoptosis-related genes (NOD2, DUSP1, and ADM) and 8 genes overexpressed in AD skin lesions (CCDC109B, CCL5, CCL8, IFI35, LYN, RAB31, IFITM1, and IFITM2) were induced by IFN-γ in primary keratinocytes [33]. Modified gene expression of filaggrin, loricin, involucrin, corneodesmosin or late cornified envelope protein mirror disturbed keratinocyte differentiation in AD [34].
Not only the skin itself, but already microbes colonizing the skin represent the first line of the skin barrier. Interaction of microbes with the skin immune system is important for the pathogenesis of AD. Due to different factors, such as higher pH and a Th2 dominated micromilieu elevated amounts of Staphylococcus aureus (S. aureus) are detectable on AD skin [35, 36]. Furthermore, S. aureus dampens skin barrier function by releasing virulence factors such as α-toxin to induce cell death of keratinocytes [37] and to promote Th2-type inflammation [3825]. After treatment and improvement of skin lesions, Propionbacteriae, Corynebacteriae and Streptococci are detectable in increased amounts on AD skin [39-41]. Birth mode, birth order, number of siblings and breast feeding were identified as potential co-factors impacting on the gut microbiome. While colonization with Lactobacilli and Bacteroides increased with the number of siblings, colonization with Clostridia decreased [42].
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47. Niebuhr M, Langnickel J, Draing C et al. Dysregulation of toll-like receptor-2 (TLR-2)-induced effects in monocytes from patients with atopic dermatitis: impact of the TLR-2 R753Q polymorphism. Allergy. 2008; 63:728-734. 48. Kaesler S, Volz T, Skabytska Y et al. Toll-like receptor 2 ligands promote chronic atopic dermatitis through IL-4-mediated suppression of IL-10. J Allergy Clin Immunol. 2014; 134:92-99. 49. Brandt EB, Gibson AM, Bass S et al. Exacerbation of allergen-induced eczema in TLR4- and TRIF-deficient mice. J Immunol. 2013; 191: 3519-3525. 50. Dai X, Sayama K, Tohyama M et al. Mite allergen is a danger signal for the skin via activation of inflammasome in keratinocytes. J Allergy Clin Immunol. 2011; 127: 806-814. 51. Roth SA, Simanski M, Rademacher F et al. The pattern recognition receptor NOD2 mediates Staphylococcus aureus-induced IL-17C expression in keratinocytes. J Invest Dermatol. 2014; 134: 374-380. 52. Varga A, Budai MM, Milesz S et al. Ragweed pollen extract intensifies lipopolysaccharide-induced
priming
of
NLRP3
inflammasome
in
human
macrophages. Immunology. 2013; 138: 392-401. 53. Niebuhr M, Baumert K, Heratizadeh A et al. Impaired NLRP3 inflammasome expression and function in atopic dermatitis due to Th2 milieu. Allergy. 2014; 69: 1058-1067. 54. Berroth A, Kühnl J, Kurschat N et al. Role of fibroblasts in the pathogenesis of atopic dermatitis. J Allergy Clin Immunol. 2013; 131: 1547-1554.
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polymorphisms (SNPs) in the IFNG and IFNGR1 were significantly associated with eczema herpeticum [32], which is based on a higher susceptibility to HSV skin infection of a subgroup of AD patients. Keratinocytes of patients with AD exhibit increased IFN-γ–induced apoptosis compared with keratinocytes from healthy subjects. Three apoptosis-related genes (NOD2, DUSP1, and ADM) and 8 genes overexpressed in AD skin lesions (CCDC109B, CCL5, CCL8, IFI35, LYN, RAB31, IFITM1, and IFITM2) were induced by IFN-γ in primary keratinocytes [33]. Modified gene expression of filaggrin, loricin, involucrin, corneodesmosin or late cornified envelope protein mirror disturbed keratinocyte differentiation in AD [34].
Not only the skin itself, but already microbes colonizing the skin represent the first line of the skin barrier. Interaction of microbes with the skin immune system is important for the pathogenesis of AD. Due to different factors, such as higher pH and a Th2 dominated micromilieu elevated amounts of Staphylococcus aureus (S. aureus) are detectable on AD skin [35, 36]. Furthermore, S. aureus dampens skin barrier function by releasing virulence factors such as α-toxin to induce cell death of keratinocytes [37] and to promote Th2-type inflammation [3825]. After treatment and improvement of skin lesions, Propionbacteriae, Corynebacteriae and Streptococci are detectable in increased amounts on AD skin [39-41]. Birth mode, birth order, number of siblings and breast feeding were identified as potential co-factors impacting on the gut microbiome. While colonization with Lactobacilli and Bacteroides increased with the number of siblings, colonization with Clostridia decreased [42].
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At present, data about the skin microbiome are premature and there is not much detailed knowledge about differences of the skin microbiome during different stages of AD and which components besides S. aureus might promote the disease.
Immune reactivity Innate immunity in the pathogenesis of AD Expression and function of pattern recognition receptors on skin cells in AD is altered due to genetic modification [43] but also due to secondary factors such as cytokines and chemokines in the micromilieu [44, 45]. TLR signalling is not only important for host defence mechanisms of the innate immune system but also for the epidermal barrier function [40]. Moreover, activation of TLR2 on monocytes and Mɸs of patients with AD leads to different cytokine and chemokine responses as compared to healthy individuals [45, 47]. So far, it is not completely clear, which mechanisms control the development of acute AD to chronic AD. A recent study demonstrates that activation of TLR2 on DCs converts Th2 type dermatitis to chronic cutaneous inflammation in a mouse model [48]. Concerning TLR4, in an allergen-induced mouse model, mice deficient of TLR4 display more severe AD-like symptoms and skin inflammation [49]. Accumulating evidence indicates that inflammasomes are involved in the pathogenesis of AD. Activation of the inflammasome in keratinocytes by allergens [50] and S. aureus [51], as well as in Mɸs after exposure to ragweed pollen allergen has been shown [52]. Current knowledge suggests inflammasomes promote Th1- or Th17-mediated inflammation that may be important for acute AD [51, 53]. Moreover, expression of human β-defensins and cathelicidins is lower in AD skin as in other chronic inflammatory skin diseases [1]. The reduced expression has been
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linked to a higher risk of AD patients to develop bacterial or viral skin infections and results in part from the Th2 dominated micromilieu in AD skin.
Functions of skin immune cells in the pathogenesis of AD Inflammatory AD skin contains vast numbers of resident and infiltrated immune cells, such as LCs, inflammatory epidermal dendritic cells (IDECs), Mɸs, MCs, neutrophils, basophils, eosinophils, Innate lymphoid cells (ILCs), natural killer cells, fibroblast [54] and various T cell subsets. Functional interactions of skin immune cells are essential for the pathogenesis of AD. The role of IgE in AD is still a matter of debate, since it is not clear if it plays a central role in the pathogenesis of AD or just a bystander phenomenon. In fact, allergen specific IgE to food or aeroallergens is detectable in a subgroup of patients with AD and allergen challenge in form of oral provocation or epicutaneous exposure leads to development or impairment of skin lesions. Among skin immune cells, DCs are the most important cell type to initiate Th2 immune responses [5, 55-56]. A hallmark of epidermal and dermal DCs in AD is the expression of the high affinity receptor for IgE (FcεRI) on the cell surface. Receptor expression increases with severity of the skin lesions and enable the cells to take up IgE and via IgE allergens [5]. After allergen challenge or onset of inflammation due to other trigger factors, the number of Langerin- DCs, FcεRI+ DC increases in the epidermis and dermis. Inflammatory DCs are regarded as main amplifier of allergic inflammation on the level of DCs. In vitro studies demonstrated that allergen challenge of inflammatory DCs subtypes increases the release of pro-inflammatory cytokines and chemokines [5]. As a result, allergen specific T cells expressing skin
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homing factor CLA are detectable in skin lesions of AD patients with clinically relevant sensitizations after allergen challenge [57, 58]. Structural similarities between exogenous proteins, of which several have been identified, and endogenous proteins have introduced the concept of IgE autoreactivity in a subgroup of atopic dermatitis patients. In a recent systematic review of 8 studies involving 634 atopic dermatitis patients and 173 control subjects, auto-IgE to keratinocyte-derived self-antigens were observed in 38.2% of the patients, most of whom were adults with persistent moderate to severe disease [59]. Thus, the time point of development of IgE autoreactivity and its contribution to the chronicity of atopic dermatitis needs to be investigated in further studies.
A recent 3D skin structure study demonstrates that in AD skin, LCs are present in the higher layers of the epidermis and penetrate skin TJ to sense outside antigen with their dendrites, while inflammatory DC subtypes are located at lower parts, suggesting different pathophysiological functions of LCs and inflammatory DCs [60, 61]. Together, current results support a model in which LCs provide important regulatory functions in a steady state, while they are also capable to contribute to T cell responses upon activation. Human monocytes are regarded as precursors of Mɸs and DCs for a long time because monocytes differentiate into Mɸs and DCs under an inflammatory milieu. Recent studies add new information by showing that in (1) normal tissue resident LCs and Mɸs are derived embryonically and renew themselves via proliferation [62, 63] and (2) in steady-state, monocytes migrated from blood to tissue keep their monocytic character, and present tissue antigen to draining lymph nodes (LNs) [64]. Therefore, attenuated IFN-γ [65] and TGF-β [66] signaling and responsiveness of human monocytes from AD patients might promote Th2 immune responses due to This article is protected by copyright. All rights reserved.
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decreased TGF-β signalling on one hand and impaired Th1 cytokine IFN-γ stimulation on the other hand. MCs are the key cells to mediate type I hypersensitivity reactions. Results from animal models demonstrate MCs are required for the development of AD-like skin lesion [67]. Number of MCs in lesional AD skin is increased, in particular of mast cells releasing IL-31, which supports the hypothesis that MCs promote skin inflammation in AD [68]. In AD skin, δ-toxin released by S. aures stimulates MC degranulation, which promotes local inflammation by release of proinflammatory mediators [69]. The role of basophils in AD is still unclear [68]. Recently, ILCs have been observed to infiltrate AD skin and to release Th2 type cytokines IL-5, IL-9 and IL-13 to promote local inflammation after stimulation with allergen, TSLP or IL-33 [70, 71]. IL-4 and IL-13 are the main mediators of Th2 driven immune response and signalling of both cytokines take part via the common IL-4 receptor α (IL-4Rα). IL4Rα mediates among several other mechanisms IgE production by B cells, dendritic cells differentiation, activation of T cells as well as recruitment of eosinophils. Consequently, inhibition of IL-4Rα mediated mechanisms would represent an plausible therapeutic target, which is currently under investigation in ongoing clinical studies [72, 73].
Interplay of immune responses in the pathogenesis of AD skin Upon stimulation with allergens, skin barrier derived-TSLP stimulates DCs to derive Th2 responses [27, 74]. Dramatic infiltration of Th2 T cells into acute AD skin, together with moderate infiltration with Th22 cells and few Th17 cells was observed. Data from atopy patch testing and other studies have proven that chronic AD is
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associated with a mixed immune response consisting of Th2/Th1/Th22 cells infiltrating the skin [34, 75] (Figure 2). Relatively small numbers of Th17 cells are present in AD skin, but the function of IL17 in the pathogenesis of AD is unclear. The observation that IL-17A suppresses expression of TSLP and Th2 cytokines, and Th2 cytokine IL-4 suppresses IL-17A function in a human skin model [76] suggests that the Th17 and Th2 pathways might coregulate each other. However, IL-17A deficient mice display attenuated Th2 responses in the acute phase of skin inflammation [77]. More results from other animal models and human systems are necessary to unravel the role of Th17 cells in AD. Interestingly, IL25 (IL-17E), an important and distinct member of the IL17 family, promotes Th2 cell-mediated inflammation by activating Th2 memory cells together with TSLP-activated DCs [78]. Furthermore, IL-25 decreases filaggrin synthesis in keratinocytes [79]. IL-33 and TSLP are tissue derived cytokines which are essential for the pathogenesis of AD by promoting local Th2 cell derived inflammation [80].
Moreover, histamine, which is released by MCs upon allergen challenge but also by other skin cells might activate macrophage like cells and promote the release of inflammatory cytokines via histamine receptor expression on the surface of those cells [81]. The chemokine pattern of DCs subsets differs profoundly between acute and chronic AD and non-lesional AD skin. Chemokines such as CCL17, CCL22 increase in the skin during inflammation and drive the recruitment of inflammatory DCs subtypes as well as T cell infiltration [82]. Data from in vitro studies with skin DCs indicate that unstimulated DCs of AD patients are capable to drive either Th1,
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Th2 or Th17 immune responses, while the local micromilieu impacts on their T cell polarization in vivo [83].
Microbiology Risk factors for complications A subgroup of patients with AD is at risk for the development of severe disseminated virus infections of the skin induced by herpes simplex virus, called eczema herpeticum (EH). From the clinical features, these patients display higher specific and total IgE serum levels. Furthermore, SNPs in IFNG and IFNGR1 as well as interferon regulatory factor (IRF)2 were associated with EH [32, 84]. Attenuated responsiveness of DCs isolated from lesional AD skin mirrored by lower STAT1 phosphorylation and induction of IFN-γ regulated genes has been demonstrated and might result from the Th2 dominance as well as support the Th2 dominance in AD skin [65]. In addition, higher IL-25 expression in the skin of patients with AD who underwent one or more episodes of EH has been identified as another risk factor. In vitro, IL-25 in combination with IL-4 or IL-13 enhances HSV replication and reduces filaggrin break down products, which have been demonstrated to counteract HSV and vaccinia replication [85]. Elevated number of functional Tregs as well as CD14dimCD16+ monocytes with attenuated capacity to produce proinflammatory cytokines has been demonstrated in acute EH [86].
Conclusion Pathogenesis of AD results from genetic, environmental as well as immunological factors. Vast immune cell types spatially and temporally coordinate each other in
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inflammatory AD skin. Further identification of this interplay on the organic, cellular and molecular level will help to develop new therapeutic approaches.
Figures Figure 1. Graphic summary of effects of skin barrier on the pathogenesis of AD. Genetic and immunologic as well as mechanical factors such as scratching induce skin barrier damage, allowing contact of skin resident antigen presenting cells to allergens, bacterial and viral antigens as well as other environmental factors. Activated antigen presenting cells migrate to lymph nodes and prime naive T cells into Th2 cells. Elevated Th2 cytokines together with TNF-α and IFN-γ further damage skin barrier functions by inducing apoptosis of keratinocytes as well as impair the function of tight junctions, and promote Th2 responses by enhancing TSLP expression of epithelial cells. Moreover, colonizing pathogens such as S. aureus impair barrier function through the release of virulence factors to induce keratinocyte death and to boost Th2-type inflammation. Together, genetic and immunological factors contribute to the skin barrier dysfunction and play a major role in the pathogenesis of AD.
Figure 2. Summary of pathogenetic mechanisms in acute and chronic AD. (a). In the acute phase of AD, high amount of invading allergens through damaged skin barrier stimulates mast cells to degranulate and to release inflammatory mediators such as histamine, PGD2, IL-6, IL-8 and TNF-α as well as IL-31. Damaged skin epithelial cells release TSLP which further enhances Th2 type skin inflammation. In response to invading allergens, skin resident LCs and keratinocytes release inflammatory cytokines including IL-12 and IL-18 as well as chemokines to attract other types of immune cells, such as Mɸs, basophils, eosinophils and neutrophils as This article is protected by copyright. All rights reserved.
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well as T cells. Although Th1, Th2, Th17 and Th22 responses co-exist in acute AD skin, Th2 type responses contribute mainly to the pathogenesis of acute AD by mediating type 2 skin inflammation. (b). Th1, Th2, Th17 and Th22 responses are involved in the pathogenesis of chronic AD. Proinflammatory cytokines such as IL-12 and IL-18 secreted by skin DCs support Th1 activation. IFN-γ secreted by Th1 cells induces keratinocyte apoptosis, while activation of Th22 cells induces skin remodeling and thickness of chronic AD skin.
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80. Kinoshita H, Takai T, Le TA et al. Cytokine milieu modulates release of thymic stromal lymphopoietin from human keratinocytes stimulated with double-stranded RNA. J Allergy Clin Immunol. 2009; 123:179. 81. Novak N, Peng WM, Bieber T et al. FcεRI stimulation promotes the differentiation of histamine receptor 1-expressing inflammatory macrophages. Allergy. 2013; 68:454-461. 82. Gros E, Bussmann C, Bieber T et al. Expression of chemokines and chemokine receptors in lesional and nonlesional upper skin of patients with atopic dermatitis. J Allergy Clin Immunol. 2009; 124: 753-760. 83. Fujita H, Shemer A, Suárez-Fariñas M et al. Lesional dendritic cells in patients with chronic atopic dermatitis and psoriasis exhibit parallel ability to activate T-cell subsets. J Allergy Clin Immunol. 2011;128:574-582. 84. Gao PS, Leung DY, Rafaels NM et al. Genetic variants in interferon regulatory factor 2 (IRF2) are associated with atopic dermatitis and eczema herpeticum. J Invest Dermatol. 2012; 132:650-657. 85. Kim BE, Bin L, Ye YM et al. IL-25 enhances HSV-1 replication by inhibiting filaggrin expression, and acts synergistically with Th2 cytokines to enhance HSV-1 replication. J Invest Dermatol. 2013; 133: 2678-2685. 86. Takahashi R, Sato Y, Kurata M et al. Pathological role of regulatory T cells in the initiation and maintenance of eczema herpeticum lesions. J Immunol. 2014; 192: 969-978.
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